Explanation of the unpredictable hepatotoxicity following use of commonly employed halogenated anesthetics remains the keystone of this investigation. Two animal models of halothane induced hepatotoxicity have been developed: 1) the PCB-model (pretreatment of rats with Aroclor 1254 prior to 1 percent halothane anesthesia for 2 hr) and 2) the hypoxic model: The hypoxic model is now being routinely used in this laboratory because of its clinical correlations. Rats are pretreated with phenobarbital and then anesthetized with 1 percent halothane for 2 hr at reduced oxygen tension (14 percent O2, 85 percent N2). The lesion that develops within 24 hr post anesthesia resembles the human situation (elevated SGPT and SGOT, extensive centrolobular necrosis). The halothane-induced liver lesion in the hypoxic model correlates well with the increased bioactivation of halothane in phenobarbital pretreated animals, particularly when in vitro microsomal studies are performed under N2 or when 14C-halothane is administered to rats maintained at 14 percent O2. Investigations in the coming year will focus on determining: 1) if a reductive pathway is involved in bioactivation of halothane; 2) if microsomal inducing agents or inhibition influence this bioactivation and halothane hepatotoxicity; 3) if liver necrosis can be prevented by pretreatment of rats with free radical scavengers or membrane stabilizers; 4) if the hypoxic model is common to many species and 5) the genetic and environmental factors that may predispose an individual to halothane-induced hepatotoxicity. BIBLIOGRAPHIC REFERENCES: Sipes, IG, Brown BR Jr: An animal model of hepatotoxicity associated with halothane anesthesia. Anesthesiology 45:622-628, 1976.